CD4 T Cells Specific for Different Pathogens Vary in Susceptibility to HIV Infection

By Richard Jefferys

February 6, 2013

When it comes to susceptibility to HIV infection, not all CD4 T cells are created equal. There are a variety of factors that have been shown to influence how readily HIV gains entry and replicates, with the best-described distinction being between activated CD4 T cells, which are highly susceptible, and resting CD4 T cells, which are relatively resistant. The particular types of cytokines and chemokines that a CD4 T cell makes have also been shown to influence the efficiency of HIV infection. Less well understood is the influence of antigen specificity -- the pathogen being targeted by the CD4 T cell. Evidence has been published showing that TB-specific CD4 T cells are highly susceptible, whereas those responding to the viral infection CMV are relatively resistant (with this resistance being associated with the release of beta-chemokines capable of binding the CCR5 receptor and blocking HIV entry). A study by Haitao Hu and colleagues from the U.S. Military HIV Research Program has now explored this issue further by looking at the susceptibility of various pathogen-specific CD4 T cells and the relationship with the genes that the different cells express.

The results confirm that CMV-specific CD4 T cells are highly resistant to HIV, but not just due to the release of beta-chemokines: gene expression analyses revealed that the cells also upregulate several innate antiviral factors such as IFIT1 (a protein that recognizes a particular form of viral RNA). Because of these factors, CMV-specific CD4 T cells displayed reduced susceptibility to HIV infection even when the researchers used antibodies to neutralize any effect of beta-chemokines. In contrast, CD4 T cells specific for tetanus toxoid (TT) and Candida exhibited a pro-inflammatory Th17-type profile and were highly permissive to HIV infection. The researchers suggest that these differences in susceptibility may contribute to the well-documented relationship between differing levels of immune deficiency and risk of specific opportunistic infections; i.e., candidiasis is typically an early sign of immune deficiency whereas active CMV disease occurs almost exclusively at extremely low CD4 T-cell levels.

Another important implication of the study is that HIV vaccines should aim to induce HIV-specific CD4 T cells with a profile that resembles CMV-specific responses. The researchers speculate that there may be a connection between their observations and the fact that the best results obtained to date in the stringent SIV/macaque model of vaccination have involved a CMV-based vaccine vector. Several research groups -- including those of Louis Picker at the Oregon Health & Science University and Rafick-Pierre Sékaly at the Vaccine & Gene Therapy Institute of Florida -- are now working to develop CMV-based HIV vaccine vectors with the aim of conducting human studies in both the therapeutic and preventive contexts.

This article was provided by Treatment Action Group. It is a part of the publication Michael Palm HIV Basic Science, Vaccines & Prevention Project Weblog.
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